A novel, facile, rapid, solvent free protocol for the one pot green synthesis of chromeno[2,3-d]pyrimidines using reusable nano ZnAl₂O₄ – a NOSE approach and photophysical studies

Abstract

The current protocol resulted in the preparation of an eco-friendly, highly stable, reusable nano ZnAl₂O₄ and for the first time this was used as an excellent catalyst for the pseudo four component synthesis of a library of fluorescent chromeno[2,3-d]pyrimidine derivatives. This novel protocol involved the grinding of salicylaldehydes, malononitrile and secondary amines in the presence of a catalytic amount of nano ZnAl₂O₄ at room temperature which was an extremely simple, facile, cost effective, solvent free protocol and also required just two minutes to achieve the products with excellent yields. The synthesized chromeno[2,3-d]pyrimidine derivatives showed significant absorption and emission properties and large Stoke's shift values due to their characteristic feature of an excited state intramolecular proton transfer (ESIPT) mechanism. Nano ZnAl₂O₄ exhibited better catalytic activity than that of the bulk due to its larger surface area of 63 m² g⁻¹, and was recycled 5 times without loss of activity.

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Introduction

The development of a facile, efficient protocol for multi-component reactions (MCRs) which meet the credentials of green chemistry aspects as well as cost effectiveness has gained great importance in synthetic as well as medicinal chemistry. MCRs involving carbon–carbon,¹ carbon–oxygen² and carbon–nitrogen³ bond formation are very attractive as they allow synthesizing a wide range of complicated medicinal scaffolds.⁴ It is extremely important to explicate a protocol which can construct such complex molecules in a single step using reusable heterogeneous, inexpensive catalyst in a simple solvent-free rapid procedure at room temperature, with excellent yields. In recent years, nano metal oxides have attracted much attention as excellent catalysts for MCRs because of their high thermal,⁵ chemical stability,⁶ large surface area,⁷ high efficiency⁸ and ease of separation from the reaction mixture.⁹ Being cheap¹⁰ and environmentally benign,¹¹ these nano metal oxides facilitate the reactions as they possess active sites on their surface¹² by bringing the reactants close to each other, and thus accelerate the reaction rate¹³ and also provide reusability,¹⁴ high selectivity¹⁵ and excellent yields in shorter duration.¹⁶ Nanomaterials have been employed to mimic the homogeneous catalysts for MCRs to carry out at room temperature and thus these materials could be the alternative catalysts for homogeneous catalysts.¹⁷

Chromeno[2,3-d]pyrimidine derivatives are the important class of compounds constructed by the fusion of chromenes and pyrimidines. These are the potential candidates, which exhibit in vivo antitumor activity, cytotoxic activity against P388 lymphocytic leukemia by causing significant perturbation in cell cycle kinetics, and also by being selectively active against a number of human ovarian cell lines.¹⁸ Chromeno[2,3-d]pyrimidines possess in vitro activity against both Gram positive and negative bacteria.¹⁹ The derivatives with this moiety are also active against fungi and their antimicrobial activities are higher than that of 4H-chromenes.¹⁹ In addition, these molecules exhibit excellent photophysical properties but detailed study has not been carried out so far.²⁰

Chromeno[2,3-d]pyrimidine moiety was reported by O'Callaghan by the condensation of 2-iminocoumarin-3-carboxamide with aldehyde, which involves multistep reaction procedure.²¹ LiClO₄ has been used as catalyst for the synthesis of chromeno[2,3-d]pyrimidine derivatives but it requires 15 h of stirring.²² There are only few reports in the literature for the synthesis of chromeno[2,3-d]pyrimidines by the one pot tandem condensation of salicylaldehydes, malononitrile and secondary amines: high temperature solvent-free microwave assisted synthesis,²³ expensive [Bmim]BF₄ ionic liquid,²⁴ less active heterogeneous catalyst²⁵ and magnetic nanomaterial²⁶ synthesis. Homogeneous Lewis acid catalysts such as CuCl, ZnCl₂ and ZrOCl₂·8H₂O have been used for this synthesis. Even though this protocol involves room temperature synthesis, it takes long time to achieve the good yields and the catalysts are not reusable.²⁰

Keeping the drawbacks of existing methods in our mind for the synthesis of chromeno[2,3-d]pyrimidines, we prepared ZnAl₂O₄ nanoparticles and employed them as catalyst for MCRs. We developed a new protocol for the pseudo four component synthesis of chromeno[2,3-d]pyrimidines using salicylaldehydes, malononitrile and secondary amines. The protocol demonstrated was a room temperature synthesis, rapid, solvent free, environmentally benign and cost effective method. The catalysts were chemically stable and also reused successfully for 5 cycles. To the best of our knowledge, we report nano ZnAl₂O₄ for the first time for the pseudo four component synthesis of library of fluorescent chromeno[2,3-d]pyrimidines synthesis.

Results and discussion

Characterization of nano ZnAl₂O₄

Fig. 1a shows that the synthesized fresh nano ZnAl₂O₄ was phase pure, and was crystallized in face centered cubic phase with the diffraction peaks at 2θ = 19.0, 31.3, 36.8, 44.8, 49.1, 55.6, 59.3, 65.3, 74.2 and 77.3 which were indexed based on ICDD data (# 821043). The average crystallite size of nano ZnAl₂O₄ was calculated using full width half maximum values in Scherrer's formula and was found to be 20 nm which corroborates the TEM result. Fig. 1b affirms that the nano ZnAl₂O₄ was stable even after 5 cycles. BET surface area of the catalyst was 63 m² g⁻¹. FTIR spectrum of the nano ZnAl₂O₄ is shown in Fig. 2. It gives the bands at 662 cm⁻¹, 558 cm⁻¹ and 501 cm⁻¹ corresponding to stretching and bending modes of Al–O of octahedral AlO₆ units respectively. The absence of stretching vibration bands of inverse spinel units (AlO₄) in the range 700–850 cm⁻¹ confirms ZnAl₂O₄ was purely normal spinel structure.²⁷ EDX spectrum (Fig. 2), confirmed the presence of atoms Zn, Al and O in the catalyst. TEM images (Fig. 3) affirmed that the particles exhibited oval shape and found in the range 6–20 nm (the inset in Fig. 3). Selected area electron diffraction pattern (SAED) indicated the presence of pure and crystalline spinel ZnAl₂O₄.

Fig. 1 Powder X-ray diffraction pattern of fresh nano ZnAl₂O₄ (a) and after 5 cycles (b).

Fig. 2 FTIR spectrum of nano ZnAl₂O₄ (left) and EDX spectrum of nano ZnAl₂O₄ (right).

Fig. 3 TEM images and SAED pattern of nano ZnAl₂O₄.

Catalytic role and optimization of nano ZnAl₂O₄ on the synthesis of chromeno[2,3-d]pyrimidines

In the initial phase, we planned to study the catalytic role of nano ZnAl₂O₄ on one-pot pseudo four component reactions of salicylaldehyde, malononitrile and secondary amine as shown in Scheme 1. We focused our attention on designing and generalizing the optimal conditions of the reaction. At first, in order to carry out the synthesis of chromeno[2,3-d]pyrimidine derivatives in a more efficient way, the reaction among salicylaldehyde (2 mmol), malononitrile (1 mmol) and morpholine (1 mmol) was selected as a model reaction at room temperature (Scheme 2). Without catalyst, the reaction did not proceed by grinding or stirring conditions and even with ethanol as solvent. Very low yields were obtained by employing bulk Al₂O₃ as a catalyst in ethanol. Then we attempted preliminary screening tests of catalysts using bulk and nano-Al₂O₃, ZnO, ZnAl₂O₄, and these tests are summarized in Table 1. Significant improvements in the yields were observed when the reaction conditions were switched from bulk Al₂O₃ to nano-Al₂O₃ under same experimental conditions. But when we carried out the same reaction in ethanol by using bulk ZnO as a catalyst, interestingly yields were moderately increased with reduced reaction time. Almost similar results were obtained using nano ZnO as a catalyst. By keeping these interesting key properties in our mind, i.e., significant yield improvement using nano-Al₂O₃ and reduction in the time taken for the completion of reaction using ZnO, it was of interest to design spinel ZnAl₂O₄ for employing as a catalyst for these MCRs.

Scheme 1 Nano ZnAl₂O₄ catalyzed synthesis of chromeno[2,3-d]pyrimidine derivatives under solvent free conditions.

Scheme 2 Nano ZnAl₂O₄ catalyzed synthesis of chromeno[2,3-d]pyrimidines using salicylaldehyde, malononitrile and morpholine.

Table 1 Screening of the catalyst for one-pot synthesis of chromeno[2,3-d]pyrimidines^a

Entry	Nano catalyst^a	Solvent^i		Without solvent
				Stirring		Grinding
		Time (min)	Yield (%)	Time (min)	Yield (%)	Time (min)	Yield (%)
a Reaction conditions: salicylaldehyde (2 mmol), malononitrile (1 mmol), morpholine (1 mmol) and catalyst (20 mol%) in 10 mL solvent; a: 20 mol% catalyst loaded; b: bulk; c: acidic; d: basic; e: 5 mol% catalyst loaded; f: 10 mol% catalyst loaded; g: 15 mol% catalyst loaded; h: 25 mol% catalyst loaded; i: ethanol used as solvent; n: nano.
1	No catalyst	720	10	720	ND	720	ND
2	Al2O3(b, n)^c	720	25, 45	720	12, 29	30	10, 28
3	Al2O3(b, n)^d	720	30, 47	720	10, 32	30	10, 27
4	ZnO(b, n)	360	61, 63	360	68, 69	30	71, 78
5	ZnAl2O4(b, n)	60, 30	66, 86	30, 2	84, 93	30, 2	80, 96
6	ZnAl2O4(b, n)^e	75, 30	10, 25	45, 30	25, 44	45, 30	5, 40
7	ZnAl2O4(b, n)^f	60, 30	30, 50	30, 10	39, 70	30, 10	35, 60
8	ZnAl2O4(b, n)^g	60, 30	55, 78	30, 5	77, 88	30, 5	79, 90
9	ZnAl2O4(b, n)^h	60, 30	65, 84	30, 2	83, 89	30, 2	81, 95

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In order to study the catalytic role of bulk ZnAl₂O₄, a controlled experiment was carried out by adopting the above model reaction conditions by stirring at room temperature using appropriate 20 mol% catalysts (Table 1, entry 1). Under these conditions, the reaction proceeded moderately with 66% yield and took less reaction time compared to ZnO. With the same standard conditions, when nano ZnAl₂O₄ was employed as a catalyst, surprisingly 86% of desired chromeno[2,3-d]pyrimidine 4a was obtained within 30 min. This was because of the higher surface area of nano ZnAl₂O₄ (63 m² g⁻¹) when compared to bulk ZnAl₂O₄ (10.4 m² g⁻¹). In order to study the effect of quantity of nano ZnAl₂O₄ on the reaction, we monitored the same reaction using 5, 10, 15, 20 and 25 mol% of nano ZnAl₂O₄ catalyst and found that the quantity of catalyst had a significant effect on the formation of the desired product. The use of 5 mol% and 15 mol% of nano-ZnAl₂O₄ resulted in low yields (Table 1, entries 6 and 8). Whereas, 86% of the desired product 4a was obtained by employing 20 mol% of nano-ZnAl₂O₄ at room temperature (Table 1, entry 5).

In order to achieve high yield in a shorter duration, we performed the reactions in various solvents at room temperature as well as under reflux conditions. A range of nonpolar to polar solvents such as toluene, chloroform, dioxane, tetrahydrofuron, ethanol, methanol and acetonitrile were used for these MCRs, but there was no significant effect on the yields of product even after few hours (Table 2). Unsatisfied with these results, we also tested the influence of solvent-free conditions on the reaction rate and yield by screening several conditions at room temperature in the presence of ZnAl₂O₄ nanoparticles and found that the product formation took place rapidly under solvent-free stirring conditions than in the presence of a solvent (Table 1). Satisfactory results were obtained with the use of liquid reactants but moderate yields were achieved with solid reactants due to the improper mixing of solid reactants, which in turn reduced the feasibility to react each other due to heterogeneity. To overcome this drawback, a systematic procedure was followed. Mixture of salicylaldehydes (2 mmol), malononitrile (1 mmol), and nano ZnAl₂O₄ catalyst (20 mol%) in mortar was well ground with pestle at room temperature for 60 s. Then the secondary amine (1 mmol) was added to the well ground reaction mixture which resulted in a vigorous exothermic reaction within few seconds. Realizing this catalytic enhancement of the MCRs reaction by nano-ZnAl₂O₄ with this ‘NOSE’ approach, the desired chromeno[2,3-d]pyrimidine derivatives were obtained up to 97% yield in 2 min reaction time under solvent-free grinding conditions.

Table 2 Effect of solvents on the synthesis of chromeno[2,3-d]pyrimidines

Sl no.	Solvent	Yield^a^,^b (%)
a Under room temperature.b Under reflux conditions; reaction conditions: salicylaldehyde (2 mmol), malononitrile (1 mmol), morpholine (1 mmol) and nano ZnAl2O4 catalyst (20 mol%) in 10 mL solvent.
1	Toluene	59, 61
2	Chloroform	60, 62
3	Dioxane	69, 68
4	Tetrahydrofuran	66, 70
5	Ethanol	86, 86
6	Methanol	81, 85
7	Acetonitrile	79, 80

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To estimate the scope and generality of the NOSE protocol, 2-hydroxy aromatic aldehydes having both electron-withdrawing and electron-donating groups were allowed to react with an active methylene compound malononitrile and secondary amine based nucleophile like morpholine, piperidine, 1-phenylpiperazine, 1-benzylpiperazine, N-benzhydrylpiperazine, pyrrolidine, diethyl amine, n-ethylaniline, and n-ethyltoluidine under optimized reaction conditions. The results are depicted in Table 4. The reaction proceeded smoothly with the substituted salicylaldehydes i.e., 4a, 4b, 4c, 4d, 4e yielding 96, 94, 89, 93, 89% respectively except 4f which yielded only 72%. Similarly, the reaction with the cyclic secondary amines such as 4a, 4g, 4k, 4l, 4m gave better yields of 96, 97, 85, 89, 90% respectively when compared to dialkyl substituted amines such as 4q, 4r giving 81, 80% respectively. No products were obtained with the use of alkyl–aryl substituted amines. The reactions were consistently carried out at 1 mmol scale, and no change of product yield was observed when scaled up to 10 mmol scale under the same reaction conditions.

The plausible mechanism for the formation of chromeno[2,3-d]pyrimidine was proposed according to the literature. Initially the condensation of salicylaldehyde 1 and malononitrile 2 yielded Knoevenagel product 5, which upon subsequent Pinner reaction formed cyclized product 6. The reaction was initiated by catalytic nucleophilic attack of amines 3 on the cyano group of cyclized product 6 to produce intermediate 7. Finally, intermediate 7 reacted with another molecule of salicylaldehyde 1 followed by proton transfer of 4A to result in the product 4 with recyclable nano catalyst (Scheme 3). We assumed that the nano ZnAl₂O₄ initiated both Knoevenagel condensation of salicylaldehyde with malononitrile and nucleophilic attack of secondary amine as it possess Lewis acidic Zn²⁺ and Al³⁺ sites.⁷ It is known from the previous report that the Lewis acid catalysts facilitate chromeno[2,3-d]pyrimidines synthesis and the zinc based catalyst is more reactive.²⁰

Scheme 3 Plausible mechanism for nano ZnAl₂O₄ catalyzed synthesis of chromeno[2,3-d]pyrimidines.

To examine the reusability of nano ZnAl₂O₄, the catalyst was collected by filtration after every cycle and it was washed with chloroform, tetrahydrofuran and acetone (each 5 mL) to remove the organic compound and dried overnight in the oven at 60 °C before it was used for the next cycle. To check the reusability of ZnAl₂O₄ nano, we have chosen nano ZnAl₂O₄ and was found to be consistently active for 5 cycles (Fig. 4). AAS was used to find out the leaching of ions after each cycle, and it was found to be nil. We made a comparison of our protocol with the reported protocols (Table 3). It is understood that although there are few solvent free, short duration protocols for the synthesis of chromeno[2,3-d]pyrimidine available in literature, they suffer from drawbacks such as, high temperature reactions, use of expensive and non-reusable catalysts. Nano ZnAl₂O₄ took the shortest duration to synthesize these derivatives with reusability.

Fig. 4 Reusability of nano ZnAl₂O₄ for the synthesis of chromeno[2,3-d]pyrimidines using salicylaldehyde, malononitrile and morpholine.

Table 3 Comparison of the activity of the catalysts for the synthesis of chromeno[2,3-d]pyrimidine derivatives

Sl no.	Catalyst	Solvent	Temperature/reaction condition	Reaction time	Yield (%)	Reference
a 1-Butyl-3-methylimidazolium tetrafluoroborate.
1	LiClO4	C2H5OH	RT/stirring	15 h	74–80	22
2	—	—	100 °C/microwave oven	3–6 min	86–96	20
3	[Bmim]BF4^a	—	RT/stirring	20 min	65–90	21
4	CuCl, ZnCl2	CH2Cl2, CH3OH	80 °C/reflux	7 h	72	16
			80 °C/reflux	4 h	80
5	Aminopropyl coated Fe3O4	—	RT	7 min	87–89	22
6	Nano ZnAl2O4	—	RT	2 min	72–97	Present work

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Photophysical study of chromeno[2,3-d]pyrimidines

The spectral properties of the compounds such as absorption (λ_max), emission (λ_em), Stoke's shift and molar extinction coefficient (ε) were measured in tetrahydrofuran, and they are summarized in Table 4. The absorption and fluorescence spectra of all the products dissolved in tetrahydrofuran are shown in Fig. 5a and b respectively. All the compounds showed absorption with maximum wavelength ranging from 285 to 360 nm. Most of the derivatives displayed two absorption maxima except 4f, 4h and 4i which showed single band. Highest energy absorption band I in the region of 280–300 nm and lowest energy absorption band II in the region of 315–360 nm were observed. The lowest energy transition band II could be attributed to the transition from singlet ground (S₀) to the first excited state (S₁) S₀ → S₁. The increase in conjugation and increased electron density associated with salicylaldehyde groups and presence of alkyl groups in amine moiety in chromeno[2,3-d]pyrimidines led to bathochromic shift of the absorption maxima in compounds 4b, 4q and 4r.

Table 4 Photophysical properties of nano-ZnAl₂O₄ catalyzed chromeno[2,3-d]pyrimidine derivatives^a

Entry	Aldehyde	Amine	Product	Yield (%)	Solution	Solid state		Δ (cm^−1)
						λabs (nm)	λem (nm)
a Yields refer to isolated products after purification by recrystallization.
1	1a	3a	4a	96	290, 320	485	499	10 631
2	1b	3a	4b	94	300, 355	445	509, 554	10 861
3	1c	3a	4c	89	290, 325	401	503	5831
4	1d	3a	4d	93	295, 315	476	498	10 737
5	1f	3a	4e	89	295, 330	493	500	10 019
6	1e	3b	4f	72	295	490	—	13 490
7	1a	3b	4g	97	295, 320	496	491	11 089
8	1c	3b	4h	93	285	402, 457	512	13 206
9	1d	3b	4i	92	295	478	516	12 978
10	1f	3b	4j	91	290, 330	496	507	10 142
11	1a	3c	4k	85	295, 320	498	508	11 170
12	1a	3d	4l	89	295, 320	501	505	11 290
13	1a	3e	4m	90	280, 320	496	500	11 089
14	1a	3f	4n	91	295, 320	470	477	9973
15	1c	3f	4o	89	295, 315	499	509	11 706
16	1d	3f	4p	87	290, 320	494	503	11 007
17	1c	3g	4q	81	295, 360	474	555	6681
18	1f	3g	4r	80	290, 330	495	492	10 101
19	1a	3h	4s	nd	—	—	—	—
20	1a	3i	4t	nd	—	—	—	—

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Fig. 5 (a) UV-vis spectra (b) fluorescence spectra of compounds 4a–r recorded in tetrahydrofuran solution (5 × 10⁻⁵ M).

The most notable feature was the exited state intramolecular proton transfer (ESIPT) mechanism that occurred in all the compounds studied, and emission was observed from the excited state of the keto form with fluorescence excitation wavelength (λ_ex) of 330 nm, which is shown in Fig. 6. It can be understood from Fig. 5b that the compounds are fluorescent in solution and most of the compounds displayed almost similar emission spectra in the range of 475–500 nm with the exception of 4b and 4c which showed hypsochromic shift of the emission maxima. The compound 4h showed two emission maxima ranges of 402 nm and 457 nm which was 94 nm blue shifted when compared 4g. The chromeno[2,3-d]pyrimidines were strongly fluorescent in solid state and the compounds showed strong, bright green emission with a maximum range of 490–510 nm in the solid state. The corresponding solid state fluorescence spectrum is given in Fig. 7. The fluorescence maxima of the derivatives except 4g and 4r were bathochromically shifted in solid state when compared to emission maxima in solution. In solid state, compounds 4b and 4q bathochromically shifted with the emission maxima of 554, 555 nm respectively and 4n was hypsochromically shifted with the emission maxima of 477 nm when compared to 4a. Interestingly, compound 4l showed high emission maxima in solid state, and donor–acceptor type fluorophores based on 4l were synthesized and detailed photophysical studies are under progress. The compound 4f was not fluorescent in solid state. The Stoke's shift value was calculated to be 10 631 cm⁻¹ for molecule 4a. The higher Stoke's shift and molar extinction coefficient value suggested significant structural changes between the ground and excited states. Further, the large emission shift from absorption maximum may be due to the presence of –OH group connected to quinoline ring at 4^th position through intervening π-conjugation probably inducing the exited state intramolecular proton transfer character which would also be responsible for the observed larger Stoke's shift values as the characteristic features of ESIPT mechanism.

Fig. 6 The energy diagram of ESIPT process showing tautomeric structures of 4g with normal and ESIPT fluorescence.

Fig. 7 Fluorescence spectra of compounds 4a–r recorded in solid state.

Conclusion

In the current study, we successfully prepared the ZnAl₂O₄ nanoparticles with 6–20 nm size. We developed a simple grinding method for the pseudo four component synthesis of chromeno[2,3-d]pyrimidines at room temperature. The advantages of this method are: the catalyst nano ZnAl₂O₄ is non-toxic, inexpensive and chemically highly stable, reusable without loss of activity and the method is novel, facile, rapid, green, solvent-free, and a cost effective. Workup is simple and yields are high in short duration. No column chromatography is required. The prepared new chromeno[2,3-d]pyrimidines showed excellent fluorescent properties which can be used in fluorescence based sensor applications.

Experimental section

General information

Zinc nitrate (Zn(NO₃)₂·6H₂O) and aluminium nitrate (Al(NO₃)₃·9H₂O) were purchased from Himedia. Acrylamide (C₃H₅NO). N,N′-methylenebisacrylamide (C₇H₁₀N₂O₂) and ammonium peroxodisulphate were purchased from Sigma Aldrich. Starch was purchased from SD fine Chemicals. Organic chemicals were purchased from Sigma Aldrich, Merck and Himedia. Purity of all the chemicals was greater than 99%. The phase formation of nano ZnAl₂O₄ was inferred by Bruker D8 Advanced powder X-ray diffractometer using Cu Kα (λ = 1.5406 Å) radiation. The diffraction angle 2θ measurements were obtained in the range of 10–70° at room temperature. The catalyst was further characterized by Fourier Transformed Infrared Spectra (FTIR) on Shimadzu IR affinity – 1 FTIR spectrometer by KBr disk method. BET surface area of the nano ZnAl₂O₄ was found from nitrogen adsorption desorption isotherms on Micromeritics ASAP 2020 V3.00H instrument. Elemental analysis of the nano ZnAl₂O₄ was performed by Field Emission Scanning Electron Microscope coupled with Energy Dispersive X-ray Analysis (FESEM-EDX) on JEOL JSM 7001F with BRUKER-QUNTAX Version 1.8.2. Transmission electron microscopic (TEM) images of the catalyst were received on JEOL 3010 instrument with UHR pole piece to find out morphology and particle size. Concentration of leached metal ions of the catalyst after every cycle of the reaction was tested by Atomic Absorption Spectroscopic technique using Varian AA240 instrument. ¹H and ¹³C NMR spectra were taken on Bruker 300 MHz using CDCl₃ and DMSO-d₆ as the solvent with TMS as an internal standard. Melting points were measured on Guna capillary based melting point apparatus and were not corrected. HRMS values were obtained on Joel GC Mate II GC-Mass Spectrometer. FTIR spectra of the synthesized organic compounds were recorded using a Jasco-4100 spectrometer instrument. UV-Visible spectra were taken using Hitachi U-2910 spectrophotometer. Fluorescence spectra in solution and solid were measured using Hitachi F-7000 fluorescence spectrometer.

Synthesis of ZnAl₂O₄

Nano ZnAl₂O₄ was synthesized by modifying our previous method.⁷ 1 : 2 molar ratio of aqueous solution of zinc nitrate (Zn(NO₃)₂·6H₂O) and aluminium nitrate (Al(NO₃)₃·9H₂O) were added drop wise to 25% starch solution followed by 1 : 1 ratio of acrylamide and N,N′-methylenebisacrylamide under constant stirring and heating. A pinch of ammonium peroxodisulphate was added to the above homogeneous solution when the temperature reached 80 °C. The resulted gel was heated overnight at 80 °C, and the obtained black mass was calcined at 300 °C, 500 °C and 700 °C for 6 h with intermittent grinding. For comparison of activity of catalysts, we prepared bulk ZnAl₂O₄ by our previous method.⁷

General procedure for the synthesis of chromeno[2,3-d]pyrimidine derivatives

In a typical synthesis, 20 mol% of nano ZnAl₂O₄ was placed in a mortar. To this, salicylaldehyde (1) (2 mmol) was introduced, followed by malononitrile (2) (1 mmol). The entire mixture was well ground at room temperature for 60 s. A vigorous exothermic reaction took place when the secondary amine (3) (1 mmol) was added to the well ground reaction mixture. Grinding of the mixture for another 60 s led to the formation of desired products. Completion of the reaction was monitored by TLC. The catalyst was separated using Whatman filter paper by dissolving the reaction mixture in tetrahydrofuran. The solvent was removed by evaporation, and the crude solid product was purified by a recrystallization procedure in tetrahydrofuron and ethanol. In order to reuse the catalyst for the next cycle, the catalyst was washed with chloroform, tetrahydrofuron and acetone (each 5 mL), which was later dried overnight at 60 °C and reused for the next cycle.

2-(4-Morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4a). Yellow solid; melting point: 197–199 °C: IR (KBr): 3375, 3024, 2949, 2779, 1753, 1708, 1560, 1388, 1246, 1209, 1161, 1118, 1008, 920, 767, 671 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.46–3.43 (t, J = 6.0 Hz, 4H), 3.74–3.72 (t, J = 8.0 Hz, 4H), 3.94 (s, 2H), 6.87–6.83 (t, J = 8.0 Hz, 2H), 7.13–7.07 (m, 2H), 7.24–7.20 (t, J = 8.0 Hz, 2H), 7.33–7.29 (q, J = 4.0 Hz, 2H), 8.20–8.18 (d, J = 2.0 Hz, 1H), 13.03 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.6, 48.0, 65.9, 97.6, 116.3, 117.3, 118.0, 118.8, 119.8, 124.5, 128.1, 128.6, 129.0, 132.9, 149.7, 159.7, 160.5, 163.1, 164.0; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 361.1426, found 361.1420.

1-(11-Morpholino-12H-benzo[5,6]chromeno[2,3-d]pyrimidin-9-yl)naphthalen-2-ol (4b). Brown solid; melting point: 180–182 °C: IR (KBr): 3377, 3051, 2970, 2845, 1737, 1622, 1588, 1537, 1425, 1404, 1365, 1228, 1111, 925, 821, 746, 518 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.65 (s, 4H), 3.88 (s, 4H), 4.36 (s, 2H), 7.24–7.22 (d, J = 8.0 Hz, 1H), 7.36–7.32 (t, J = 8.0 Hz, 1H), 7.43–7.41 (d, J = 8.0 Hz, 1H), 7.59–7.48 (m, 3H), 7.70–7.66 (t, J = 8.0 Hz, 1H), 7.84–7.82 (d, J = 8.0 Hz, 1H), 7.98–7.89 (m, 5H), 8.08–8.06 (d, J = 8.0 Hz, 1H), 9.00–8.98 (d, J = 8.0 Hz, 1H), 12.96 (s, 1H); HRMS for C₂₇H₂₁N calculated [M⁺] m/z 461.1739, found 461.1741.

2-Methoxy-6-(9-methoxy-4-morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4c). Pale yellow solid; melting point: 198–200 °C: IR (KBr): 3311, 3023, 2848, 1737, 1546, 1435, 1369, 1273, 1240, 1203, 1078, 1016, 742, 737, 665 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.50–3.49 (m, 4H), 3.91–3.89 (m, 4H), 3.94–3.93 (m, 8H), 6.79–6.77 (d, J = 8.0 Hz, 1H), 6.88–6.84 (t, J = 8.0 Hz, 1H), 6.98–6.96 (d, J = 8.0 Hz, 1H), 7.07–7.03 (t, J = 8.0 Hz, 1H), 8.10–8.08 (d, J = 8.0 Hz, 1H), 13.67 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 25.7, 30.9, 48.7, 56.0, 56.1, 66.6, 97.8, 110.7, 114.1, 117.9, 118.5, 119.8, 119.9, 121.1, 124.3, 140.0, 148.2, 148.7, 150.7, 162.4, 164.4; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 421.1638, found 421.1640.

2-Ethoxy-6-(9-ethoxy-4-morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4d). Yellow solid; melting point: 120–122 °C: IR (KBr): 3247, 3037, 2978, 2922, 2893, 284, 2183, 1714, 1649, 1579, 1544, 1438, 1394, 1271, 1238, 1111, 1008, 732 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.42–1.38 (t, J = 8.0 Hz, 3H), 3.51 (s, 2H), 3.81 (s, 2H), 4.05–4.00 (m, 6H), 7.09–6.75 (m, 6H), 7.86–7.84 (d, J = 8.0 Hz, 1H), 13.35 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 14.6, 14.8, 24.8, 38.8, 39.0, 39.2, 39.4, 39.7, 39.9, 40.1, 48.1, 97.5, 111.8, 116.0, 117.9, 118.1, 120.0, 120.7, 124.3, 139.1, 146.6, 147.7, 150.4, 160.8, 163.31, 163.8; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 449.1951, found 449.1958.

4-Bromo-2-(7-bromo-4-morpholino-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4e). Yellow solid; melting point: 194–196 °C: IR (KBr): 3333, 3015, 2970, 2850, 1737, 1541, 1477, 1417, 1352, 1273, 1244, 1116, 1068, 956, 867, 731, 626 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.52 (m, 4H), 3.82 (m, 4H), 4.03 (s, 2H), 6.88–6.86 (d, J = 8.0 Hz, 1H), 7.15–7.13 (d, J = 8.0 Hz, 1H), 7.48–7.41 (m, 2H), 7.56 (s, 1H), 8.31–8.30 (d, J = 4.0 Hz, 1H), 13.08 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.5, 48.0, 65.9, 97.5, 109.9, 116.1, 118.4, 119.7, 122.3, 130.4, 130.7, 131.4, 135.1, 148.9, 158.9, 159.4, 162.8, 163.9; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 516.9637, found 516.9639.

4-Nitro-2-(7-nitro-4-(piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4f). Yellow solid; melting point: 262–264 °C: IR (KBr): 3346, 3071, 2927, 2858, 2677, 1708, 1602, 1517, 1336, 1244, 1182, 1064, 842, 742, 688 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.76 (s, 6H), 2.51 (s, 2H), 3.53 (s, 4H), 4.10 (s, 2H), 7.03–7.00 (t, J = 8.0 Hz, 1H), 7.35–7.33 (d, J = 8.0 Hz, 1H), 7.98–7.97 (d, J = 8.0 Hz, 1H), 8.26–8.10 (m, 3H), 9.10 (s, 1H), 14.19 (s, 1H); HRMS for C₂₇H₂₁N calculated [M⁺] m/z 449.1335, found 449.1333.

2-(4-(Piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4g). Yellow solid; melting point: 166–168 °C: IR (KBr): 3373, 3045, 2926, 2852, 2229, 1722, 1602, 1588, 1446, 1257, 1186, 1051, 970, 758, 690, 582 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.78–1.75 (m, 6H), 3.45–3.42 (t, J = 6.0 Hz, 4H), 3.92 (s, 2H), 6.93–6.89 (t, J = 8.0 Hz, 1H), 6.98–6.96 (d, J = 8.0 Hz, 1H), 7.12–7.08 (t, J = 8.0 Hz, 1H), 7.26–7.18 (m, 3H), 8.36–8.32 (t, J = 8.0 Hz, 1H), 8.43–8.41 (d, J = 8.0 Hz, 1H), 13.45 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.3, 25.6, 25.9, 49.5, 97.5, 117.1, 117.5, 118.6, 118.8, 119.5, 124.4, 128.2, 128.5, 129.2, 132.8, 150.6, 160.4, 162.0, 164.4, 165.2; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 359.1634, found 359.1632.

2-Methoxy-6-(9-methoxy-4-(piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4h). Pale yellow solid; melting point: 181–183 °C: IR (KBr): 3345, 3043, 2931, 2841, 1570, 1541, 1438, 1394, 1365, 1276, 1234, 1099, 1062, 954, 740, 682 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.71 (m, 2H), 1.76 (m, 4H), 3.42 (m, 4H), 3.91 (s, 2H), 3.93 (s, 6H), 6.78–6.76 (d, J = 8.0 Hz, 1H), 6.86–6.81 (m, 2H), 6.97–6.95 (d, J = 8.0 Hz, 1H), 7.05–7.01 (t, J = 8.0 Hz, 1H), 8.11–8.09 (d, J = 8.0 Hz, 1H), 14.00 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.3, 25.7, 25.9, 49.5, 56.0, 56.0, 97.5, 110.5, 113.8, 117.7, 118.7, 119.8, 120.5, 121.1, 124.1, 140.2, 148.1, 148.7, 150.7, 162.2, 164.5, 164.9; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 419.1845, found 419.1849.

2-Ethoxy-6-(9-ethoxy-4-(piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4i). Yellow solid; melting point: 100–102 °C: IR (KBr): 3273, 3041, 2976, 2929, 2848, 1722, 1588, 1544, 1471, 1440, 1387, 1273, 1219, 1199, 1070, 1020, 897, 777 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.70 (t, 6H), 3.49 (m, 4H), 3.81 (m, 4H), 3.95 (s, 4H), 3.99 (s, 2H), 6.94–6.83 (m, 3H), 7.00–6.98 (d, J = 8.0 Hz, 1H), 7.12–7.05 (m, 2H), 8.90–8.88 (d, J = 8.0 Hz, 1H), 13.52 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 23.8, 24.9, 25.4, 48.7, 55.7, 55.7, 97.1, 114.8, 117.8, 118.1, 120.0, 120.0, 120.8, 124.3, 139.1, 147.4, 148.5, 150.3, 160.7, 164.1; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 447.2158, found 447.2157.

4-Bromo-2-(7-bromo-4-(piperidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4j). Yellow solid; melting point: 226 °C: IR (KBr): 3310, 3062, 2937, 2848, 2320, 1541, 1438, 1421, 1367, 1348, 1213, 1182, 1060, 971, 817, 744, 665, 623 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.71 (m, 6H), 3.48 (s, 4H), 4.00 (s, 2H), 6.88–6.86 (d, J = 8.0 Hz, 1H), 7.15–7.13 (d, J = 8.0 Hz, 1H), 7.48–7.42 (m, 2H), 7.58 (s, 1H), 8.31–8.30 (d, J = 4.0 Hz, 1H), 13.28 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 23.7, 24.6, 25.4, 48.7, 78.5, 78.9, 79.2, 97.2, 116.0, 118.4, 119.7, 119.8, 122.6, 130.4, 130.7, 131.4, 135.1, 149.1, 158.9, 159.3, 162.9, 164.1; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 514.9844, found 514.9848.

2-(4-(4-Phenylpiperazin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4k). Yellow solid; melting point: 212–214 °C: IR (KBr): 3337, 3031, 2885, 2833, 2731, 1737, 1597, 1577, 1490, 1429, 1365, 1247, 1180, 1012, 950, 815, 758, 695 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.41 (s, 4H), 3.71 (s, 4H), 4.03 (s, 2H), 6.93–6.86 (m, 3H), 7.01–6.99 (d, J = 8.0 Hz, 2H), 7.16–7.12 (m, 2H), 7.36–7.25 (m, 5H), 8.38–8.36 (d, J = 8.0 Hz, 1H), 13.13 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 25.0, 47.6, 48.5, 97.3, 115.7, 116.3, 117.1, 118.0, 118.3, 118.9, 119.6, 124.1, 127.8, 128.4, 128.6, 128.7, 132.4, 149.8, 150.4, 159.8, 161.1, 163.5, 164.2; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 436.1899, found 436.1896.

2-(4-(4-Benzylpiperazin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4l). White solid; melting point: 136–138 °C: IR (KBr): 3357, 3012, 2926, 2808, 2736, 1708, 1579, 1529, 1436, 1253, 997, 835, 748, 695. cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 2.58 (s, 4H), 3.54 (s, 4H), 3.58 (s, 2H), 3.99 (s, 2H), 6.95–6.92 (t, J = 6.0 Hz, 2H), 7.20–7.14 (m, 2H), 7.30–7.27 (t, J = 6.0 Hz, 2H), 7.39–7.34 (m, 6H), 7.28–7.26 (d, J = 8.0 Hz, 1H), 13.16 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.7, 25.1, 47.7, 52.4, 61.9, 66.9, 97.4, 116.3, 117.3, 118.1, 118.8, 119.9, 124.5, 127.0, 128.1, 128.2, 128.6, 128.9, 129.0, 132.8, 137.8, 149.8, 159.7, 160.5, 163.2, 163.9; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 450.2056, found 450.2054.

2-(4-(4-Benzhydrylpiperazin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4m). Pale yellow solid; melting point: 198–200 °C: IR (KBr): 3367, 3024, 2954, 2877, 2841, 2382, 1735, 1597, 1546, 1489, 1429, 1384, 1284, 1217, 1138, 997, 956, 742 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.59 (s, 8H), 3.96 (s, 2H), 4.40 (s, 1H), 6.93–6.89 (t, J = 8.0 Hz, 2H), 7.38–7.12 (m, 12H), 7.51–7.49 (m, 4H), 7.26–7.24 (d, J = 8.0 Hz, 1H), 13.16 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.7, 47.7, 51.4, 74.9, 97.4, 116.3, 117.3, 118.0, 118.8, 119.9, 124.57, 126.9, 127.6, 128.1, 128.6, 129.0, 132.9, 142.6, 149.7, 159.7, 160.5, 163.2, 163.9; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 526.2369, found 526.2369.

2-(4-(Pyrrolidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4n). Yellow solid; melting point: 186–188 °C: IR (KBr): 3317, 3043, 2968, 2870, 1602, 1543, 1448, 1436, 1390, 1259, 1134, 958, 839, 748 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.94 (m, 4H), 3.80 (s, 4H), 4.32 (s, 2H), 6.92–6.88 (t, J = 8.0 Hz, 2H), 7.14–7.12 (d, J = 8.0 Hz, 2H), 7.29–7.25 (m, 2H), 8.37–8.33 (t, J = 8.0 Hz, 1H), 8.30–8.28 (d, J = 8.0 Hz, 1H), 13.53 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.3, 24.9, 46.0, 49.3, 91.8, 116.1, 117.2, 118.2, 118.5, 119.8, 124.2, 128.0, 128.5, 129.2, 132.5, 149.5, 159.9; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 345.1477, found 345.1478.

2-Methoxy-6-(9-methoxy-4-(pyrrolidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4o). Yellow solid; melting point: 158–160 °C: IR (KBr): 3369, 3051, 2968, 1737, 1548, 1536, 1435, 1396, 1240, 1211, 1138, 983, 777 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.72 (s, 6H), 3.83–3.79 (m, 8H), 4.18 (s, 2H), 6.70–7.11 (m, 5H), 7.80–7.78 (d, J = 8.0 Hz, 1H), 13.85 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.8, 25.1, 40.1, 49.2, 55.4, 55.6, 79.0, 110.2, 118.2, 120.0, 138.8, 147.1, 150.4, 160.6; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 405.1689, found 405.1698.

2-Ethoxy-6-(9-ethoxy-4-(pyrrolidin-1-yl)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4p). Yellow solid; melting point: 178–180 °C: IR (KBr): 3367, 3031, 2974, 2927, 2868, 1717, 1598, 1579, 1537, 1444, 1242, 1211, 1112, 1060, 929, 773, 675 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 3.03 (m, 6H), 3.57 (m, 6H), 3.91 (s, 4H), 4.17 (s, 2H), 7.11–7.10 (d, J = 4.0 Hz, 1H), 7.31–7.27 (t, J = 8.0 Hz, 2H), 7.81.7.56 (m, 4H), 9.43–9.41 (d, J = 8.0 Hz, 1H), 13.94 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 22.3, 48.2, 66.2, 76.9, 77.2, 77.5, 110.9, 116.9, 119.2, 121.7, 122.5, 124.6, 125.5, 126.7, 126.8, 128.0, 128.4, 128.6, 133.1, 159.7; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 433.2002, found 433.2010.

2-(4-(Diethylamino)-9-methoxy-5H-chromeno[2,3-d]pyrimidin-2-yl)-6-methoxyphenol (4q). Yellow solid; melting point: 170–172 °C: IR (KBr): 3377, 3045, 2977, 2322, 2212, 1726, 1637, 1595, 1489, 1371, 1255, 1197, 1149, 1118, 1049, 923, 752, 615 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.77–1.72 (m, 6H), 3.42 (s, 4H), 3.93 (s, 8H), 6.82–6.79 (d, J = 8.0 Hz, 1H), 6.87–6.85 (t, J = 4.0 Hz, 2H), 6.97–6.95 (d, J = 8.0 Hz, 1H), 7.06–7.04 (t, J = 8.0 Hz, 1H), 8.12–8.10 (d, J = 8.0 Hz, 1H), 14.0 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.3, 25.7, 25.9, 29.7, 49.6, 56.0, 56.1, 97.5, 110.5, 113.8, 117.7, 118.7, 119.8, 120.5, 121.1, 124.1, 140.2, 148.2, 148.7, 150.7, 162.2, 164.6, 165.0; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 407.1845, found 407.1847.

4-Bromo-2-(7-bromo-4-(diethylamino)-5H-chromeno[2,3-d]pyrimidin-2-yl)phenol (4r). Yellow solid; melting point: 180–182 °C: IR (KBr): 3329, 3059, 2964, 2864, 1737, 1595, 1539, 1481, 1421, 1377, 1257, 1214, 1103, 966, 812, 731, 628, 538 cm⁻¹: H¹NMR (400 MHz, CDCl₃)™ ppm: 1.96 (s, 6H), 3.79 (s, 4H), 4.03 (s, 2H), 6.87–6.85 (d, J = 8.0 Hz, 1H), 7.10–7.08 (d, J = 8.0 Hz, 1H), 7.49–7.39 (m, 3H), 8.28 (s, 1H), 13.54 (s, 1H); C¹³NMR (100 MHz, CDCl₃)™ ppm: 24.6, 48.0, 65.9, 97.6, 116.3, 117.3, 118.0, 118.8, 119.8, 124.6, 128.1, 128.6, 129.0, 132.9, 149.7, 159.7, 160.5, 163.1, 164.0; HRMS for C₂₇H₂₁N calculated [M⁺] m/z 502.9844, found 502.9856.

Acknowledgements

Balijapalli Umamahesh and Triveni Rajashekhar Mandlimath thank CSIR for providing Senior Research Fellowship. The DST-FIST NMR facility at VIT University and VIT management are duly acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: NMR copies of synthesized compounds were included. See DOI: 10.1039/c4ra16263c

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